We propose to study the sequence of alterations in metabolism and function that occurs in cells during the O-2 toxicity. The hypothesis to be tested is that reversible metabolic changes in the cellular antioxidant defenses allow oxygen-induced irreversible loss of cellular functions. This will be tested in cell types with reported differences in resistance to O-2 toxicity: rat and guinea pig alveolar macrophages and rat granular pneumocytes (type II cells). The cells will be exposed in vitro for O-48 and assays made for: NADPH, glutathione, mixed disulfides, ascorbate, lipid peroxidation products, superoxide dismutase and catalase activities, ATP, ADP, Ca2+ mobilization and distribution, membrane potentials, the respiratory burst of the macrophages, and isoproterenol stimulated dipalmitoyl lecithin secretion by type II cells. Manipulation of antioxidant defenses through selenium deficiency, inhibition of superoxide dismutase and catalase, glutathione depletion, and augmentation of antioxidant enzymes and/or mimetics with liposomes will be used to alter the rates of change in metabolism and function. Both the respiratory burst and Beta-adrenergic stimulated dipalmitoyl lecithin secretion are under regulatory control involving several of the parameters that we will be measuring. Comparison of the rates of alterations in cellular activities in both single cell types and between these cell types should reveal: (a) the sequence of events in O-2 toxicity; (b) which alterations are crucial in development of toxicity or resistance to hyperoxia; and (c) the interrelationships of functions in regulatory processes. The methodology includes spectrophotometric, fluorometric and chemiluminescence assays, HPLC, distribution of radiolabeled ions, radiolabeled precursor incorporation, and use of liposomes. Our long-term objective is an understanding of the molecular mechanisms in normal regulatory and toxicologic processes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Toxicology Subcommittee 2 (TOX)
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Children's Hospital of Los Angeles
Los Angeles
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Forman, Henry Jay (2016) Redox signaling: An evolution from free radicals to aging. Free Radic Biol Med 97:398-407
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Rahman, Irfan; Biswas, Saibal K; Jimenez, Luis A et al. (2005) Glutathione, stress responses, and redox signaling in lung inflammation. Antioxid Redox Signal 7:42-59

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